ArticleNucleic acids research2007
A novel mechanism of selectivity against AZT by the human mitochondrial DNA polymerase.
Article in Nucleic acids research, 2007. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 33 papers.
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Who cites it
33 citing papers in PubMed.
- Slow PPThe Journal of biological chemistry · 2026Article
- Measurement of Nucleotide Hydrolysis Using Fluorescent Biosensors for Phosphate.Methods in molecular biology (Clifton, N.J.) · 2021Article
- Modulating the DNA polymerase β reaction equilibrium to dissect the reverse reaction.Nature chemical biology · 2017Article
- Structural Insights into the Post-Chemistry Steps of Nucleotide Incorporation Catalyzed by a DNA Polymerase.Journal of the American Chemical Society · 2017Article
- Rate-limiting Pyrophosphate Release by HIV Reverse Transcriptase Improves Fidelity.The Journal of biological chemistry · 2016Article
- Thumb Site 2 Inhibitors of Hepatitis C Viral RNA-dependent RNA Polymerase Allosterically Block the Transition from Initiation to Elongation.The Journal of biological chemistry · 2016Article
- Insights into the Molecular Mechanism of Polymerization and Nucleoside Reverse Transcriptase Inhibitor Incorporation by Human PrimPol.Antimicrobial agents and chemotherapy · 2016Article
- Klenow Fragment Discriminates against the Incorporation of the Hyperoxidized dGTP Lesion Spiroiminodihydantoin into DNA.Chemical research in toxicology · 2015Article
- Requirement for transient metal ions revealed through computational analysis for DNA polymerase going in reverse.Proceedings of the National Academy of Sciences of the United States of America · 2015Article
- DNA polymerase γ and disease: what we have learned from yeast.Frontiers in genetics · 2015Review
- Elucidation of kinetic mechanisms of human translesion DNA polymerase κ using tryptophan mutants.The FEBS journal · 2014Article
- Structure and mechanism of DNA polymerase β.Biochemistry · 2014Article
- TDP1 repairs nuclear and mitochondrial DNA damage induced by chain-terminating anticancer and antiviral nucleoside analogs.Nucleic acids research · 2013Article
- Article
- Kinetic characterization of exonuclease-deficient Staphylococcus aureus PolC, a C-family replicative DNA polymerase.PloS one · 2013Article
- Perspective: pre-chemistry conformational changes in DNA polymerase mechanisms.Theoretical chemistry accounts · 2012Article
- Metabolism of deoxypyrimidines and deoxypyrimidine antiviral analogs in isolated brain mitochondria.Journal of neurochemistry · 2012Article
- Metal-induced DNA translocation leads to DNA polymerase conformational activation.Nucleic acids research · 2012Article
- Effect of the Y955C mutation on mitochondrial DNA polymerase nucleotide incorporation efficiency and fidelity.Biochemistry · 2011Article
- Role of induced fit in limiting discrimination against AZT by HIV reverse transcriptase.Biochemistry · 2011Article
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2 authors.
Funding
Abstract
Native nucleotides show a hyperbolic concentration dependence of the pre-steady-state rate of incorporation while maintaining concentration-independent amplitude due to fast, largely irreversible pyrophosphate release. The kinetics of 3'-azido-2',3'-dideoxythymidine (AZT) incorporation exhibit an increase in amplitude and a decrease in rate as a function of nucleotide concentration, implying that pyrophosphate release must be slow so that nucleotide binding and incorporation are thermodynamically linked. Here we develop assays to measure pyrophosphate release and show that it is fast following incorporation of thymidine 5'-triphosphate (TTP). However, pyrophosphate release is slow (0.0009 s(-1)) after incorporation of AZT. Modeling of the complex kinetics resolves nucleotide binding (230 microM) and chemistry forward and reverse reactions, 0.38 and 0.22 s(-1), respectively. This unique mechanism increases selectivity against AZT incorporation by allowing reversal of the reaction and release of substrate, thereby reducing kcat/K(m) (7 x 10(-6) microM(-1) s(-1)). Other azido-nucleotides (AZG, AZC and AZA) and 8-oxo-7,8-dihydroguanosine-5'-triphosphate (8-oxo-dGTP) show this same phenomena.
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